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Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.

The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

Resonant optical dipole antennas, consisting either of two arms coupled by a small gap or of a single, uncoupled arm only, are fabricated by the application of electron beam lithography and gold evaporation. Using dark-field microscopy, scattering spectra of structures with varied antenna arm length and varied gap size are obtained. The results show not only a spectral redshift for coupled structures compared to single arm structures, but also that the far-field scattering intensity is significantly higher for two arm structures with gap. In addition to the dipole structures, first fabrication results on quadrupole antennas and split-ring antennas are presented, offering novel pathways for an enhancement of the optical response function.

The second order nonlinear optical (NLO) properties of two different ionic selfassembled multilayer (ISAM) films combined with Ag nanoparticles have been investigated. The plasmon resonances in the Ag particles concentrate the incident light, markedly increasing in the NLO efficiencies of the films. We find that the efficiency enhancement is significantly larger in conventional ISAM films compared to films made using a hybrid covalent ISAM technique (HCISAM), even though the intrinsic bulk second order non-linear susceptibility (χ(2)) is much larger for HCISAM films. We attribute this to the interfaces in HCISAM films being much easier to disrupt by external perturbations such as the metal deposition by which the nanoparticles are fabricated. We conclude that because the plasmon decay length is very short, the plasmonic enhancement of NLO effects primarily occurs at and near the film-particle interface. To discern the importance of the interfaces, we surrounded thin ISAM and HCISAM films with NLOinactive buffer layers, which confirmed this hypothesis, particularly in the case of HCISAM films.

A new ESCA (electron spectroscopy for chemical analysis) instrument has been developed to provide high sensitivity and efficient operation for laboratory analysis of composition and chemical bonding in very thin surface layers of solid samples. High sensitivity is achieved by means of the high-intensity, efficient X-ray source described by Davies and Herglotz at the 1968 Denver X-Ray Conference, in combination with the new electron energy analyzer described by Lee at the 1972 Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy. A sample chamber designed to provide for rapid introduction and replacement of samples has adequate facilities for various sample treatments and conditioning followed immediafely by ESCA analysis of the sample.

Examples of application are presented, demonstrating the sensitivity and resolution achievable with this instrument. Its usefulness in trace surface analysis is shown and some “chemical shifts” measured by the instrument are compared with those obtained by X-ray spectroscopy.

We observed pediatric S. aureus hospitalizations decreased 36% from 26.3 to 16.8 infections per 1,000 admissions from 2009 to 2016, with methicillin-resistant S. aureus (MRSA) decreasing by 52% and methicillin-susceptible S. aureus decreasing by 17%, among 39 pediatric hospitals. Similar decreases were observed for days of therapy of anti-MRSA antibiotics.

Objectives: Alzheimer’s disease (AD) typically eludes clinical detection for years, if not decades. The identification of subtle cognitive decline associated with preclinical AD would not only advance understanding of the disease, but also provide clinical targets to assess preventative and early intervention treatments. Disrupted retrieval of detailed episodic autobiographical memories may be a sensitive indicator of subtle cognitive decline, because this type of memory taxes a core neural network affected by preclinical AD neuropathology. Methods: To begin to address this idea, we assessed the episodic specificity of autobiographical memories retrieved by cognitively normal middle-aged and older individuals who are carriers of the apolipoprotein E ε4 allele – a population at increased risk for subtle cognitive decline related to neuropathological risk factors for AD. We compared the ε4 carriers to non-carriers of ε4 similar in age, education, and gender. Results: The ε4 carriers did not perform worse than the non-carriers on a comprehensive battery of neuropsychological tests. In contrast, as a group, the ε4 carriers generated autobiographical memories that were reduced in “internal” or episodic details relative to non-carriers. Conclusions: These findings support the notion that reduced autobiographical episodic detail generation may be a marker of subtle cognitive decline associated with AD. (JINS, 2018, 24, 1073–1183)

Improving geolocation accuracy in text data has long been a goal of automated text processing. We depart from the conventional method and introduce a two-stage supervised machine-learning algorithm that evaluates each location mention to be either correct or incorrect. We extract contextual information from texts, i.e., N-gram patterns for location words, mention frequency, and the context of sentences containing location words. We then estimate model parameters using a training data set and use this model to predict whether a location word in the test data set accurately represents the location of an event. We demonstrate these steps by constructing customized geolocation event data at the subnational level using news articles collected from around the world. The results show that the proposed algorithm outperforms existing geocoders even in a case added post hoc to test the generality of the developed algorithm.

BACKGROUND: Meningiomas are the most common primary benign brain tumors in adults. Given the extended life expectancy of most meningiomas, consideration of quality of life (QOL) is important when selecting the optimal management strategy. There is currently a dearth of meningioma-specific QOL tools in the literature. OBJECTIVE: In this systematic review, we analyze the prevailing themes and propose toward building a meningioma-specific QOL assessment tool. METHODS: A systematic search was conducted, and only original studies based on adult patients were considered. QOL tools used in the various studies were analyzed for identification of prevailing themes in the qualitative analysis. The quality of the studies was also assessed. RESULTS: Sixteen articles met all inclusion criteria. Fifteen different QOL assessment tools assessed social and physical functioning, psychological, and emotional well-being. Patient perceptions and support networks had a major impact on QOL scores. Surgery negatively affected social functioning in younger patients, while radiation therapy had a variable impact. Any intervention appeared to have a greater negative impact on physical functioning compared to observation. CONCLUSION: Younger patients with meningiomas appear to be more vulnerable within social and physical functioning domains. All of these findings must be interpreted with great caution due to great clinical heterogeneity, limited generalizability, and risk of bias. For meningioma patients, the ideal QOL questionnaire would present outcomes that can be easily measured, presented, and compared across studies. Existing scales can be the foundation upon which a comprehensive, standard, and simple meningioma-specific survey can be prospectively developed and validated.

Brain tumor behavior is driven by aberrations in the genome and epigenome. Many of these changes, such as IDH mutations in diffuse low-grade glioma (DLGG), are common amongst the same class of tumour and can be incorporated into the diagnostic criteria. However, any given tumor may have other, less common genomic aberrations that are essential for its biological behavior and may inform on underlying aberrant cellular pathways, and potential therapeutic agents. Precision oncology is a genomics-based approach which profiles these alterations to better manage cancer patients and has established itself within the practice of oncology and is slowly making its way into neuro-oncology. The BC Cancer’s Personalized OncoGenomics (POG) program has profiled 16 adult tumours originating from the central nervous system using whole genome and transcriptome analysis (WGTA), for the first time, within a meaningful clinical timeframe/setting. As expected, primary genomic drivers were consistent with their respective diagnoses, though secondary drivers were found to be unique to each tumour. Although these analyses did not result in altered clinical management for these patients, primarily due to availability of drug or clinical trials, they highlight the heterogeneity of secondary drivers in cancers and provide clinicians with meaningful biological information. Lastly, the data generated by POG has highlighted the frequency and complexity of novel driver fusions which are predicted to behave similarly to canonical driver events in their respective tumours. The information available to clinicians through POG has provided paramount knowledge into the biology of each unique tumour.

Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (investigational, extended-release of 5-fluorocytosine) into 5-fluorouracil. In preclinical models, 5-fluorouracil kills infected dividing cancer cells, myeloid derived suppressor cells and tumor associated macrophages, enabling immune activation against the tumor. In this dose ascending Ph1 trial (NCT01470794), Toca 511 was injected into the resection cavity wall of patients with rHGG, followed by courses of oral Toca FC. Additional cohorts included combination with bevacizumab or lomustine. Across the Ph1 program, the safety profile remains favorable. Objective responses (ORs) were assessed by IRR using MRI scans prior to Toca FC treatment as baseline. ORs occurred 6-19 months after Toca 511 administration, suggesting an immunologic mechanism. The ORs were observed in 4 patients with IDH1-wildtype and 2 patients with IDH1-mutant tumors, including 5 complete responses (CRs) with the investigational therapy alone, and 1 CR in combination with bevacizumab. The median duration of response (mDoR) was 35.1+ months. As of AUG2017, all responders were CR and remain alive. In a 23-patient subgroup who received high doses of Toca 511 and met Ph3 trial criteria, mOS was 14.4 months, 3-year survival rate was 26.1%, and mDoR was 35.7+ months with a durable response rate of 21.7%. Data suggest a positive association of durable response with OS.

Introduction: Over 2.6 million Hispanic/Latino construction workers (CWs) live in the US; 91% of South Florida CWs are Hispanic/Latino. CWs have higher smoking and lower cessation rates than other workers. Limited access to cessation services, worksite turnover, and lack of interventions tailored to culture/occupation hinder cessation. Partnering with worksite food trucks to deliver unique cessation interventions may improve these efforts.

Results: CWs reported tremendous job stress. Most smoking occurred during the workday and most CWs did not use nicotine replacement therapy with past quit attempts. Most CWs were open to a worksite face-to-face group cessation intervention before work (many underutilize breaks and feel pressure to keep working). CWs felt it unnecessary to tailor the intervention to Hispanics/Latinos indicating smokers are the same regardless of race/ethnicity.

Introduction: The cricothyroid membrane is used as a landmark for emergent surgical airway access. Ultrasound identification of the cricothyroid membrane is more accurate than landmarking by palpation. The objective of this study was to determine whether head of bed elevation affects the position of the cricothyroid membrane as identified by ultrasound. Methods: This was a prospective, observational study on a convenience sample of adult patients presenting to the emergency department. Participants underwent ultrasound scans by trained physicians at 0, 30 and 90 degrees head of bed elevation to identify the cricothyroid membrane. The cricothyroid membrane position identified at 0 degrees was used as a reference, and the change in position of the external landmark of the cricothyroid membrane with the patient at 30 and 90 degrees was measured. Additionally, the patients gender, age, body mass index (BMI) and Mallampati score were recorded for comparison. Linear mixed effects models with 95% confidence intervals were used to determine the effect of head of bed elevation, age, BMI and Mallampati score on the differences between measured distances. Results: One hundred and two patients were enrolled in the study. The average change in position from reference was statistically significant for both 30 degrees [2.72±0.77mm (p<0.01)] and 90 degrees [4.23±0.77mm (p<0.01)] head of bed elevation. The adjusted linear mixed effects model showed age greater than 70, BMI over 30 and higher Mallampati score were associated with greater change in distance between cricothyroid membrane landmarks. Conclusion: There was a statistically significant difference in the position of the cricothyroid membrane comparing 0 degrees to 30 and 90 degrees head of bed elevation. However, the relatively small differences suggest that this finding is not clinically relevant. Further study is required to evaluate if these differences impact the actual successful performance of cricothyrotomy.

For this study, we adapted the Montgomery Borgatta Caregiver Burden Scale, used widely in the United States, to the Saudi Arabian context. To produce an Arabic, culturally sensitive version of the scale, we conducted semi-structured interviews with 20 Saudi family caregivers. The Arabic version of the scale was tested, and participants were asked to comment on the appropriateness of items for the construct of “caregiver burden” using the repertory grid technique and laddering procedure – two constructivist methods derived from personal construct theory. From interview findings, we examined the content of the items and the caregiver burden construct itself. Our findings suggest that the use of constructivist methods to refine constructs and quantitative instruments is highly informative. This strategy is feasible even when little is known about the investigated constructs in the target culture and further elucidates our understanding of cross-cultural variations or invariance of different versions of the scale.

As approximately one-third of peer-victimized children evidence heightened aggression (Schwartz, Proctor, & Chien, 2001), it is imperative to identify the circumstances under which victimization and aggression co-develop. The current study explored two potential moderators of victimization–aggression linkages: (a) attentional bias toward cues signaling threat and (b) attentional bais toward cues communicating interpersonal support. Seventy-two fifth- and sixth-grade children (34 boys; Mage = 11.67) were eye tracked while watching video clips of bullying. Each scene included a bully, a victim, a reinforcer, and a defender. Children's victimization was measured using peer, parent, and teacher reports. Aggression was measured using peer reports of overt and relational aggression and teacher reports of aggression. Victimization was associated with greater aggression at high levels of attention to the bully. Victimization was also associated with greater aggression at low attention to the defender for boys, but at high attention to the defender for girls. Attention to the victim was negatively correlated with aggression regardless of victimization history. Thus, attentional biases to social cues integral to the bullying context differentiate whether victimization is linked to aggression, necessitating future research on the development of these biases and concurrent trajectories of sociobehavioral development.